Nonsense-mediated mRNA decay (NMD) blockage promotes nonsense mRNA stabilization in protein 4.1R deficient cells carrying the 4.1R Coimbra variant of hereditary elliptocytosis.

Madeleine Morinière, François Delhommeau, Alain Calender, Leticia Ribeiro, Jean Delaunay, Faouzi Baklouti

mRNA Metabolism in Normal and Pathological Cells, CGMC, CNRS, Université Lyon 1, Villeurbanne, France.

Blood cells, molecules & diseases 2010 Dec 15

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We describe a new approach to stabilize nonsense mRNA, based on the inhibition of the NMD mechanism, by combining cycloheximide-mediated inhibition of translation, and caffeine-mediated inhibition of UPF1 phosphorylation. This approach aimed to identify the impact of a 4.1R splicing mutation. This mutation is involved in a partial deficiency of 4.1R in the homozygous state in a patient with hereditary elliptocytosis and a moderated hemolytic anemia. We show that, in addition to two known minor shortened and stable spliceoforms, the mutation activates an intronic cryptic splice site, which results in a nonsense mRNA major isoform, targeted to degradation in intact cells by NMD. This accounts for the main cause of 4.1R partial deficiency. In a general perspective, blocking the NMD mechanism would help to identify a missing isoform, and pave the path for a molecular targeting strategy to circumvent a deleterious splicing pathway in favor of a therapeutic splicing pathway. Copyright © 2010 Elsevier Inc. All rights reserved.

Citation

Madeleine Morinière, François Delhommeau, Alain Calender, Leticia Ribeiro, Jean Delaunay, Faouzi Baklouti. Nonsense-mediated mRNA decay (NMD) blockage promotes nonsense mRNA stabilization in protein 4.1R deficient cells carrying the 4.1R Coimbra variant of hereditary elliptocytosis. Blood cells, molecules & diseases. 2010 Dec 15;45(4):284-8